Localized and systemic infections represent one of the most serious post surgical complications. Over the past fifty years tremendous advances in materials, training and antimicrobial therapies have significantly reduced the number of life-threatening post operative infections. The development of pre-sterilized disposable surgical dressings, medical instruments, gowns, drapes and other materials have helped reduce infection frequency. However, the development of improved antimicrobials represents the single most significant advance in infection control.
There are essentially three categories of antimicrobial agents: antiseptics, disinfectants and antibiotics. Antiseptics are generally defined as compounds that kill or inhibit the growth of microorganisms on skin or living tissue. Antiseptics include, but are not limited to, alcohols, chlorhexidine, iodophors and dilute hydrogen peroxide. Disinfectants are compounds that eliminate pathogenic microorganisms from inanimate surfaces and are generally more toxic, and hence more effective, than antiseptics. Representative disinfectants include, but are not limited to, formaldehyde, quaternary ammonium compounds, phenolics, bleach and concentrated hydrogen peroxide. Antibiotics are compounds that can be administered systematically to living hosts and exhibit selected toxicity, that is, they interfere with selected biochemical pathways of microorganisms at concentrations that do not harm the host. In the alternative, an ideal antibiotic will target specific metabolic pathways that are essential for the parasite, but absent in the host. Antibiotics generally work using one of four basic mechanisms of action: 1) inhibition of protein synthesis; 2) inhibition of cell wall synthesis; 3) interference with nucleic acid synthesis; and 4) altering cell membrane selective permeability. Antibiotics include, but are not limited to penicillins, aminoglycosides, tertacyclines and macrolides,
The fundamental difference between antiseptics, disinfects and antibiotics is the ability of microorganisms to develop resistance to antibiotics. The characteristics that make antiseptics and disinfectants so effective generally precludes the development of resistant microorganisms. However, disinfectants are unsuitable for use on living tissues and many antiseptics are primarily limited to localized, generally topical, applications. Consequently, most antimicrobial prophylactic and therapeutic regimens rely on antibiotics.
The microorganism's susceptibility to an antimicrobial and the ability of the antimicrobial to reach the infection site are the two most significant factors that determine antimicrobial therapy efficacy. Antimicrobial susceptibility is generally determined by culturing the organism in the laboratory and testing it against a panel of candidate drugs. However, laboratory testing can only be done if the agent causing the infection is known. When antibiotics are used prophylactically, as is the case with surgical patients, physicians generally prescribe drugs targeted to suppress the growth of the most common post surgical infectious agents. One of the most common organisms associated with surgical infections is Staphylococcus aureus. In the past, penicillin class drugs were considered the drugs of choice to thwart S. aureus infections. However, recently, many new antibiotic resistant microorganisms including penicillin resistant S. aureus have emerged making post surgical infection control even more challenging. Consequently, physicians have turned to new generations of antibiotics in response to emerging resistant strains.
Until recently, methicillin, an analogue of penicillin, was the preferred drug for treating and preventing penicillin resistant S. aureus infections. However, methicillin resistant S. aureus (MRSA) are becoming increasingly more common. Therefore, newer and more effective treatments for MRSA as well as other difficult to treat post surgical infections are in great demand.
One approach to treating and preventing the emergence of antibiotic resistant bacteria such as MRSA is to use two or more antimicrobial compounds in combination. The advantages to this approach include having a second antimicrobial present to inhibit resistant sub-population emergence during treatment and the potential for antimicrobial synergy. Antimicrobial synergy occurs when the efficacy of one antimicrobial is enhanced by another such that the total antimicrobial effect is greater than either one alone. In many cases either antimicrobial used separately may not completely eradicate the infection, but when the drugs are used in combination, powerfully efficacious antimicrobial regimens result.
However, even the most sensitive microorganisms cannot be killed by antimicrobials unless they can reach the infection site (antimicrobial bioavaliablity). Numerous factors determine antimicrobial bioavailablity including route of administration, clearance rates from the body, tissue solubility, and the degree of blood flow surrounding the infected site. Antimicrobials that are susceptible to destruction by digestive fluids, or drugs not easily absorbed in the intestines, must be administer parenterally (usually intravenously). However, regardless of the administration route, the antibiotic must survive circulation through the blood stream prior to reaching the treatment site. If the liver or kidneys rapidly removes an antimicrobial from the blood stream, or if the antimicrobial has a high affinity for blood proteins such that it is bound and inactivated by the blood, its bioavailability can be significantly reduced. This is especially true if the infection site is deep within tissues or organs that have minimal blood flow.
Deep tissue infections can result when medical implants become contaminated prior to surgical placement. When oral or parenterally administered antimicrobials fail to effectively control and eliminate the infection, the medical implant may have to be removed. Removal requires additional surgical procedures to treat the infection and re-implant the device after the infection completely resolves. Moreover, once deep tissue infections are established, long term antimicrobial therapy and hospitalization may be required. These additional procedures increase the costs associated with device implantation, subject the patient to discomfort and in rare circumstances, increase the threat of permanent disfigurement.
Coating implantable medical devices with antimicrobial compounds provides a technique for deep tissue drug delivery that can significantly reduce the risk of post implantation infections. Coating procedures should employ broad spectrum antimicrobials that are effective against most post surgical infections, especially MRSA infections. The antimicrobials need to be soluble in physiological fluids and must be stable enough to survive processing steps required to successfully coat the medical device. Ideally, a synergistic antimicrobial combination should be used. Non-limiting examples of antimicrobial combinations are described in U.S. Pat. Nos. 5,624,704 and 5,902,283, the entire contents of which are herein incorporated by reference. Moreover, the antimicrobial coating procedure must employ methods and materials that are compatible with the antimicrobial and the material used to make the medical device. Medical devices, specifically implantable types, can be fabricated from a wide variety of biocompatible compounds including metals and polymers. Each material presents its own unique challenges to material scientists when it is necessary, or desirable, to coat medical devices with bioactive materials. However, all coating methodologies share common objectives including the need to maximize expensive and labile coating solutions, minimize environmental contamination, provide the medical device with an even coating, and maintain an efficient, controlled process that complies with Federal Food and Drug Administration (FDA) Good Manufacturing Practices (GMP). Tedious manual methods of batch coating medical devices cannot achieve these goals for all medical devices on a consistent basis.
The size, shape and composition of the medical devices can significantly limit manual methods. Moreover, lot-to-lot consistency, GMP compliance and product throughput are all greatly enhanced when automated, or semi-automated, processes are involved. Moreover, non-automated processes subject expensive coating solutions to contamination and excessive waste resulting from spillage and product handling. Additionally, many polymeric compounds used to make medical devices are coated using harsh and often toxic solvent mixtures in order to imbibe the coating material into the devices. Exposure to these solvents poses a potential risk to personal, equipment and the environment that can be best minimized by coating in a closed system, a process incompatible with most manual methods.
Therefore, there is a need for methods and systems that can provide implantable medical devices with antimicrobial coatings. Moreover, there is a need for methods and systems that can provide antimicrobial coatings in a closed system that reduce exposure to toxic solvents, maintain coating solution integrity for prolonged periods, allow for maximum product throughput, provide the medical device with a consistent, even coating, minimize product handling and accomplishes these goals in an FDA GMP compliant manner.